Elderly population account for over 50% of all intensive care admissions and during their stay, up to 87% of them suffer from delirium. There is a large body of evidence demonstrating increased mortality and worse cognitive function for elderly patients who become delirious during their intensive care unit stay. While the cause of delirium is multi-factorial, inappropriate and outdated sedation methods are preventable causes. We review the current best evidences and provide what we believe are the best sedation strategies that are in line with the Society of Critical Care Medicine’s Pain, Agitation and Delirium (PAD) best practice guideline to reduce the incidence of ICU-associated delirium.

Background

The critically ill elderly patients (age 65 and older) account for 42-52% of all intensive care unit (ICU) admissions in the United States and they have to fight an uphill battle while they’re there. (1) Along with the initial insults that brought them to the ICU, they are vulnerable to various iatrogenic complications. One injury that significantly contributes to negative patient outcome is ICU-associated delirium. (2) It is estimated to affect up to 80% of all ventilated patients and this number increases to 87% for older ICU patients, which amounts to billions of dollars every year in health care costs in addition to the immeasurable burden on the patient, their family and care providers. (1)(3) Even though delirium among hospitalized older adults is highly prevalent, the exact mechanism remains still elusive despite increasing research. (3) Delirium is characterized as an acute fluctuation of mental status and cognitive function. (3)(4) Patients who are delirious can be hyperactive with features similar to those who are acutely psychotic (e.g., agitation, hallucination, delusion, and combative behavior) or hypoactive with presentations that mimic depressive mood disorder (e.g., flat-affect, inattention, disorganized thoughts and depression). (4) Often times overlooked or mistaken as simple agitation, depression or downplayed as simply confusion resulting from advanced age, it’s increasingly evident that delirium is a major contributor to increased ICU length of stay, increased likelihood of transfer to skilled nursing facility and post-traumatic stress disorder (PTSD) after discharge. (5-7)(10) Notably, among the elderly critically ill population, the duration of a patient’s delirium is positively associated with increased mortality. (8) Similarly, patients who suffered ICU-associated delirium have been noted to suffer from enduring cognitive impairment long after their ICU discharge. (6) Those who remained delirious for extended periods of time exhibited more severe level of cognitive dysfunction. (6) Despite evidence suggesting ICU-associated delirium is crucial to patient outcomes; its incidence is mostly grossly under diagnosed and therefore untreated. (5) If used properly and routinely, validated delirium screening tools such as the Confusion Assessment Method for ICU (CAM-ICU) should be able to assist clinicians to accurately identify and treat delirium. (4)

The development of ICU-associated delirium is multifactorial. For the ICU patients, endotracheal intubation, its resultant pain and discomfort and the choices of sedations providers use to maintain ventilator synchrony remain significant risk factors. (9) Pain is a major contributor to delirium and it is often overlooked by bedside nurses as well as providers. (3)(5) Patients who were later discharged from ICU often recollect the painful procedures that they endured while hospitalized and how they contributed to their distress. (3)(7) In an emergent setting, patients are being induced and then paralyzed for intubation without adequate analgesia and sedation after intubation. (11)(12) Upon arrival in the ICU, it is traditionally thought to be more beneficial to keep mechanically ventilated patients in a state of deep sedation partly so that patients won’t have recollection of their unpleasant experience. (7)(12) In order to achieve this, patients are maintained in deep sedation using sedatives such as benzodiazepines, leading to a state of unresponsiveness, except to painful stimuli. (7)(12) There is now a growing body of evidence showing that this strategy of using benzodiazepines as the primary sedation to keep patients deeply sedated while inadequately treating their pain, under dosing on analgesia, is a flawed paradigm and that leads increases time of intubation, ICU and overall hospital length of stay and mortality. (3)(7)(12)(13) To manage behavioral symptoms of delirium, anti-psychotics such as haloperidol are used although it has never been shown to decrease the duration of delirium. (14) Similar pharmacological agents (eg.,olanzapine, and quetiapine) given concomitantly with haloperidol did not shorten the duration of delirium. (14) The current evidence emphasizes optimization of analgesia and sedation along with strategies to reduce deep sedation in order to prevent ICU-associated delirium. (3)(7)(10)(12) This article will discuss the optimal sedation strategies to reduce the incidence of delirium, highlights key practice guidelines from the Pain, Agitation, Delirium (PAD) Care Bundle and explore the role of critical care nurses in its implementation.

Review of Sedation Strategies

Hypnotics or Opioids?

Benzodiazepines such as midazolam and lorazepam are the main agents used in the ICU to maintain sedation. (3)(12)(13) It acts on the BZ receptors and thus accentuates the effect of Gamma-Amino Butyric Acid(GABA) that provides a neuro-inhibitory affect that leads to sedation. (3) They also provide anxiolytic and amnesiac effects that make them favorable agents for sedation. (3) Adverse reactions include respiratory and hemodynamic depressions. (3) When used as intravenous boluses, midazolam has a short onset and short half-life (elimination half-life is between 1.5 to 2.5 hours) while lorazapam is more potent, therefore emergence from short-term sedation takes longer. (3) As a continuous infusion, the short half-life of midazolam no longer applies due to its penetration of peripheral tissues, and active metabolites. (7) In addition, the elderly are commonly more sensitive to the sedative effect of benzodiazepines due to worse hepatic function and renal insufficiency. (3) All of which contributes to delayed emergence from benzodiazepines. When comparing patients who were sedated using benzodiazepines with those maintained on non-benzodiazepines, patients who were on non-benzodiazepines had shorter duration of mechanical ventilation and ICU length of stay. (13)

Propofol is an anesthetic agent that inhibits GABA receptors thus producing its sedative effect. (2)(3)(12) Its short acting onset and half-life make it a popular agent for induction and maintenance of sedation, especially in those patients who require constant neurological assessment. (2)(3) Adverse reactions include respiratory and hemodynamic depression. (2)(3) A rare adverse reaction is propofol infusion syndrome (PRIS) which is associated with prolonged infusion time at high infusion rate. (15) Compared with benzodiazepines, propofol has not been associated with longer ICU length of stay and prolonged mechanical ventilation. (2)(3)(7)(12-13)

Dexmedetomidine (Precedex) is a selective alpha-2 agonist that produces sedation and analgesic effects. (2-3) The advantage to its use is unique in that it does not cause respiratory depression and can be used in non-intubated patients. (3) The main adverse reactions are bradycardia and hemodynamic instability that are more prevalent when bolus doses are given. (3) There is some evidence that dexmedetomidine can reduce the incidence of delirium. (2-3)(7)

Fentanyl and morphine infusions are the main mu-receptor stimulating opioids used as analgesic for ventilated patients. (2)(3) Fentanyl’s advantage is that it provides a degree of anxiolytic properties and less likely to cause hypotension. (3)(16-17) As an intravenous bolus, it also has a relatively short onset and elimination half-life (elimination half-life 2 hours). (3) However, this property is altered by impaired hepatic function and its active metabolites. (3)(16-17) The use of morphine as an infusion for sedated and ventilated patient is less recommended due to higher potential to cause delirium. (16) In addition, its vasodilatory effect makes its use less favorable in critically ill patients who are already hemodynamically unstable. (16)(18) Remifentanil is another agent used in the ICU and its favorable aspects include less active metabolites and short onset and half-life (elimination half-life 3-10 minutes).(16)(18) However, remifentanil has been associated with immunosuppression; therefore its usage in patients who are already immunosuppressed or are at risk for it should be judicious. (7)(16)(18)

Due to the high incidence of unrecognized and under-treated pain in the critically ill population, the resultant contribution to delirium and the hypnotics sparing effect of opioids, there is a movement to use analgesic as the primary sedation for mechanically ventilated patients. (5)(16-17) Several studies that have examined the feasibility, safety and efficacy of this “analgosedation” strategy have found positive results in reduction of ventilator time, incidences of delirium, hospital length of stay and long-term mortality. (6-18)

Sedation Vacation or Targeted Light Sedation?

Sedation vacation, also known as spontaneous awake trials is a strategy where heavily sedated patients are woken up daily by reducing the dosage of their sedative to the point where they’re spontaneously awake or are visibly uncomfortable. The sedation will then be restarted but at a reduced dose. (3)(19-20) Many thought this strategy would contribute to pain, agitation and PTSD in these mechanically ventilated patients. (5) However, data on this strategy showed the exact opposite effect. (7)(12)(19-20) Patients who underwent daily sedation vacation had less symptoms of PTSD upon discharge and less cognitive dysfunction. (3)(7)(19-20) In addition to more favorable neurological function, those who underwent daily sedation vacation also had fewer days mechanically ventilated, decreased length of stay and decreased long-term mortality.(19-20) A drawback of this strategy is that it resulted in increased incidences of agitation and self-extubation, however, re-intubation rate and mortality were unchanged. (19-20)

Another sedation strategy challenges the tradition of deep sedation strategy by maintaining patients on targeted light sedation at all times without the mandatory sedation vacation. (7)(19-20) Using validated sedation scales such as Richmond Agitation and Sedation Scale (RASS), patients receive either intermittent sedative boluses or only low sedative infusions to achieve a sedation level of RASS 0 to -2 (0 being awake and alert, -2 being arousable by voice). (19-22) Similar to studies on sedation vacation, the targeted light sedation strategy also achieved favorable outcomes such as less time on ventilator, less delirium and shorter length of stay. (19-20)

Interestingly, combining these two strategies does not provide a synergistic effect on delirium. 20(19) In the Sedation Lightening and Evaluation of A Protocol (SLEAP) trial, combining daily sedation vacation and targeted light sedation strategy showed no difference in time on ventilator or length of stay when compared to the control group that used only one sedation strategy. (20) Patients who were managed on the combined strategy paradoxically received more sedation due to high incidences of agitation and pain while at the same time; nurses reported increased workload and reported more ventilator issues. (20) Neither of these strategies can be used universally without discretion. (3)(19-20) For example, patients who are under neuromuscular blockade are not candidates for sedation vacations or light sedation. (3)(19-20) Patients who are withdrawing from alcohol are similarly unsuitable for the aforementioned sedation strategies. (3)(19-20)

Highlights of PAD Guidelines and Nursing Implications

The role of critical care nurse in managing mechanically ventilated patient is crucial and cannot be understated. Frequent bedside monitoring of patient’s pain, agitation and delirium levels and titrating intervention accordingly is key to the success of any sedation protocol. (3)(5)(23) It is imperative that critical care nurses across all levels become early adopters or “champions” of the PAD care bundle. Below are the highlights of the latest guidelines on managing PAD in the critical care setting espoused by the Society of Critical Care Medicine (SCCM) and the American College of Critical Care Medicine (ACCM). (3)

Pain Guidelines

Universally considered as the fifth vital sign, pain is routinely assessed and evaluated by critical care nurses. Implementation of the pain aspect of the PAD care bundle must acknowledge well-known barriers of pain management such as knowledge deficits, misconceptions about assessment, lack of experience, resistance to the use of validated tools, limited competences or assessment skills, poor communication, and not accepting patients’ descriptions of pain as the gold standard. (24) There is historical evidence that patients’ experiences of pain and distress do not fully agree with nurses’ and assistant nurses’ assessments and the staff may underestimate pain among intensive care elderly patients. (25) The PAD care bundle includes the following key points (26):

Performing routine pain assessments every 2-3 hours and more frequently as needed in all ICU patients, regardless of whether patients can self-report their pain or not.

Self-reporting is considered the “gold standard” in pain assessment.

Behavioral Pain Scale (BPS) and the Critical-Care Pain Observation Tool (CPOT) are the most valid and reliable pain assessment tools for use in ICU patients.

Patients are considered to be in significant pain if they self-report their pain intensity of 4 or greater (0–10 Numeric Rating Scale [NRS]) or have either a BPS score of 6 or greater (BPS range = 3–12) or a CPOT score of 3 or greater (CPOT range = 3–8) if they cannot self-report.

A holistic and comprehensive pain assessment that incorporates an algorithm is essential, particularly among the hospitalized older adults. (26-27) Renal and hepatic functions must be taken into considerations as well as patient and family preferences within the overall context of quality and safety.

Agitation and Sedation Guidelines

A profusion of sedation scales have been studied and used in critical care. Both the Richmond Agitation-Sedation Scale (RASS) and the Sedation-Agitation Scale (SAS) are considered the most valid and reliable subjective scales for use in critically ill adult patients. (28) It is incumbent upon critical care nurses be able to use these tools, along with other relevant tools such as the CAM-ICU with high reliability. (4)(21-23) The PAD care bundle includes the following key points (26):

Assessment and documentation of sedation/agitation must be performed in all ICU patients, using either the RASS or SAS sedation scale, at least four times per nursing shift (e.g., every 2–3 hours), and more frequently as needed.

Medication orders for sedation must have specified parameters in order to prevent oversedation.

The choice of sedative agent to use in critically ill patients must be informed by the following factors: a) the specific indications for sedation and the sedative goals for each patient; b) the compatibility between the clinical pharmacology of a sedative, its side effect profile, and the relative contraindications for its use in a critically ill patient; and c) the overall costs (not limited to pharmacy costs) associated with using a particular sedative.

With a set of sedation protocol in place, its functional implementation depends in various factors such as the critical care nurse’s judgment and acceptance of the protocol. (7) Therefore when the institution establishes a sedation protocol, it’s important to educate and gain the acceptance of the nursing staff and take into consideration the additional workload in order to plan staffing accordingly. (7)(20)(23) Sedation strategies that relies heavily on hypnotics are a practice that is engrained in many experienced clinicians; therefore introducing alternative strategies such as analgosedation might meet resistance at first. (7)(16)(20)(23) Understanding the implications of particular sedation strategies and their implications on patient outcomes is essential in translating protocols into practice.

Delirium Guidelines

ICU-associated with delirium is a major independent contributor to mortality and other negative outcomes such as prolonged duration of mechanical ventilation, prolonged hospitalization, post-discharge institutionalization, and increased health care cost, and long-term cognitive dysfunction among others. (2-3)(10)(12) The PAD care bundle includes the following key points (26):

The emphasis on non-pharmacologic strategies in the prevention and treatment of delirium rest largely within the nursing domain. The American Association of Critical Care Nurses (AACN) endorses the use of CAM-ICU or the Intensive Care Delirium Screening Checklist (ICDSC) as assessment tools. (29) Collaborative interventions such as early mobility with physical and occupational therapy have been shown to reduce ICU length of stay, reduced prevalence of delirium and lower sedative use. (30) Compliance to activity orders (e.g., out-of-bed as tolerated) requires coordinated nursing care and support from management stakeholders to maintain staffing mix that meets national benchmarks. Nurses can use motivational interactions to encourage patients to comply with exercise and activity regimen to ensure compliance.

Another nursing-sensitive aspect of delirium prevention is optimizing rest and sleep among critically ill patients. Various strategies such having patients use earplugs, clustering nursing activities, enforcing dedicated quiet times during the day and night, reduced lighting or dimming hallway lighting, and minimizing volume of staff voices have all been shown to improve sleep and reduce delirium among patients. (26)

Translation to Practice

Implementation of best practice evidence remains a challenge in health care. The current Pain, Agitation, and Delirium (PAD) Care Bundle brings special attention to the process and approach to PAD management rather than specific recommendations for using certain medications in different clinical situations. (2) For this reason, a collaborative and interdisciplinary management that is patient-centered is called for. Given the available evidence, it is recommended to implement sedation strategy that prioritizes opioid usage for pain management with judicial usage of hypnotics if not outright avoided. (3) The optimal strategy should begin at the moment of intubation. Once a patient is intubated, continuous infusion of fentanyl or remifentanyl should be initiated at an adequate rate with intermittent boluses given until the patient reports no pain or shows no sign of pain. (11) If the patient remains agitated and is refractory to verbal reassurance and opioid boluses, non-benzodiazepine hypnotics such as propofol can be given as intravenous boluses. If the decision to start continuous hypnotic infusion is made, preference should be given to drugs such as propofol and dexmedetomidine, both of which are less associated with delirium than benzodiazepines. (3)(7)(12-13) Further agitations can be managed by antipsychotics such as haloperidol. (14) Either daily sedation vacations or targeted light sedation strategy can be used but not in conjunction. (20)

Conclusion

Older adults in critical care settings remain vulnerable to delirium and more likely to have poorer outcomes. (8) Pain, agitation, and delirium are closely interwoven pathophysiologic phenomena and each one invariably impacts the outcomes of the other. Inadequate or inappropriate choices of sedation contribute to the development of delirium and poorer outcomes. (12) Benzodiazepines have been found to be associated with higher incidence of delirium, prolonged mechanical ventilation days and longer ICU days. (13) Inadequate treatment of pain also contributes to delirium and should be adequately addressed. (9) Sedation vacation and targeted light sedation are proven strategies that decrease delirium, PTSD and other long-term negative outcomes. (2-3)(12)(19-20)

It is important for clinicians to be aware of the various factors that contribute to the development of ICU delirium, optimize sedation strategies for mechanically ventilated patients to improve overall patient outcomes. The ICU PAD care bundle does not propose a specific drug treatment strategy for all ICU patients, but maintains that treatment goals focus on patients’ pain management as a priority and to use appropriate pharmacological agents that are not associated with inducing delirium to sedate patients when necessary. (26) It is essential that critical care nurses become full partners in the implementation and evaluation of the PAD care guidelines paying close attention to patterns unique to older adults.